Analginum

General characteristics. Structure:

Active ingredient: 500 mg of metamizole sodium in 1 ml of solution.

Excipient - water for injections.

Pharmacological properties:

Pharmacodynamics. Analginum is derivative pyrazyl ketone and possesses anesthetic, febrifugal and not expressed spasmolytic by actions. The action mechanism is up to the end not studied. Some results of researches show that analginum and its main metabolite (4-N-methylaminoantipyrine) possess probably both the central, and peripheral mechanism of action.

Pharmacokinetics. After intramuscular introduction it is quickly absorbed and comes to a liver where       4 methylaminoantipyrines (4-MAA) are exposed to hydrolysis with formation of an active metabolite and it demetilirutsya to the second active metabolite – 4 aminoantipyrines (4-AA), and also biotransformirutsya to inactive metabolites – 4                             formylaminoantipyrines (4-FAA) and 4 of acetylaminoantipyrine (4-AcAA). Not changed analginum is found in blood in insignificant quantities only after intravenous administration. In blood reversibly contacts proteins of plasma (4-MAA for 58%, 4-AA for 48%). Effective concentration of the sum of metabolites of analginum makes             10 mkg/ml. Toxic action is shown at concentration of metabolites over 20 mkg/ml. At repeated administration of medicine its pharmacokinetics does not change. Cumulation of drug is not noted.

The general system clearance of active metabolites 4-MAA and 4-AA makes (182,9 ± 15,1) ml/min. and (55,2 ± 6,4) ml/min. respectively. The period of their semi-elimination (T½) makes 2,5-3,0 h and 6-8 h respectively. It is removed in the form of metabolites with urine.

At patients with an abnormal liver function and kidneys at observance of the recommended mode of dosing of cumulation of invariable active agent are not noted. Changes of pharmacokinetics at children aged from 3 years, elderly persons are aged more senior than 70 years, and also during pregnancy – is not established.

Indications to use:

- an acute pain after an injury or operation;

- gripes;

- the pain caused by a tumor;

- other acute and chronic megalgias when other medical actions are not possible;

- high temperature which does not react to other measures.

Parenteral administration of medicine is used only when enteral use is impossible.

Route of administration and doses:

The dosage depends on intensity of pain, fever and individual sensitivity in response to analginum reception.

Low effective doses which control pain and fever have to be chosen.

At children for decrease in temperature, as a rule, the sufficient dose of metamizol makes 10 mg on kilogram of body weight.

The beginning of action fluctuates from 30 to 60 minutes after intake and in 30 minutes after parenteral administration.

For children and teenagers aged up to 14 years a single dose of metamizol     of 8-16 mg on kilogram of body weight. To adults and teenagers 15 years   (> are more senior than 53 kg) it is possible to accept to 1000 mg on one reception. In case of insufficient effect of a single dose, depending on the maximum daily dose, it is possible to accept the maximum single dose to 4 times a day. The table given below contains the recommended dosage and the maximum doses.

The dosage for parenteral administration makes, usually, from 6 mg to 16 mg of metamizole sodium on kilogram of body weight.

To patients aged from 3 months till 1 year metamizol is entered only intramusculary. Use of doses more than 1000 mg of metamizole sodium has to be parenterally carefully weighed in connection with possible development of hypotensive reactions.

Age (body weight)	Single dose
3-11 months (5-8 kg)	0,1-0,2 ml of analginum (50-100 mg of metamizole sodium) only intramusculary
1-3 years (9-15 kg)	0,2-0,5 ml of analginum (100-250 mg of metamizole sodium)
4-6 years (16-23 kg)	0,3-0,8 ml of analginum (150-400 mg of metamizole sodium)
7-9 years (24-30 kg)	0,4-1 ml of analginum (200-500 mg of metamizole sodium)
10-12 years (31-45 kg)	0,5-1 ml of analginum (250-500 mg of metamizole sodium
13-14 years (46-53 kg)	0,8-1,8 ml of analginum (400-900 mg of metamizole sodium)
Adults and patients are more senior than 15 years   (> 53 kg)	1-2 ml * analginum (500-1000 mg of metamizole sodium)

* - if necessary increase in a single dose up to 5 ml (that corresponds to 2500 mg of metamizole sodium) and a daily dose to 10 ml is possible (that corresponds to 5000 mg of metamizole sodium).

Elderly patients. At elderly patients the dose has to be reduced as removal of metabolites can be slowed down at analginum reception.

At depression of function of kidneys and disturbance of clearance of creatinine. At this category of patients, the dose has to be reduced as removal of metabolic products can be slowed down at metamizol reception.

Disturbance of renal or hepatic function. High doses should be avoided at reduced renal or hepatic function. Perhaps short-term use without dose decline. Prolonged use is impossible.

Way of introduction. The way of introduction depends on desirable therapeutic effect and a condition of the patient. In most cases, peroral introduction is sufficient for achievement of satisfactory effect. In need of obtaining bystry effect perhaps intravenous or intramuscular administrations of drug. At the choice of a way of introduction it is necessary to consider higher risk of development of anaphylactic or anaphylactoid reactions at parenteral administration.

Solution of analginum is entered intravenously or intramusculary (at babies (3-11 months) - only intramusculary). Temperature of the entered solution for injections has to be close to body temperature.

Injection solution of analginum it is possible to mix or part 5% with solution of glucose, 0,9% normal saline solution or Ringera-laktata solution. Due to the limited stability of these solutions, they have to be used immediately.

Because of potential incompatibility, it is not recommended to use analginum solution with other drugs with one syringe or system for intravenous infusions.

Route of administration. Duration of treatment depends on a look and disease severity. Long therapy with Analginum demands regular monitoring of indicators of blood, including calculation of a leukocytic formula.

Precautionary measures during an injection. Expediency of introduction of a single dose more than 2 ml of Analginum (1000 mg of metamizole sodium are equivalent) demands careful assessment of a ratio advantage/risk, in connection with possible development of dozozavisimy hypotension or allergic reactions. Parenteral administration of drug is carried out in position of the patient lying under careful medical observation.

To minimize risk of a sharp lowering of arterial pressure and to provide a possibility of the timely termination of administration of drug at development of anaphylactic or anaphylactoid reaction, the intravenous injection has to be carried out very slowly, with a speed no more than 1 ml a minute (that corresponds to 500 mg of metamizole sodium a minute).

Features of use:

Anesthetic contains derivative pyrazyl ketone - analginum, capable to cause rare, but life-threatening side effects in the form of shock and an agranulocytosis. In the presence at the patient of anaphylactoid reaction to analginum, it is impossible to exclude allergic reactions and to other non-narcotic analgesics.

At patients with anaphylactic or others immunological the mediated reactions (for example, an agranulocytosis) on analginum in the anamnesis, development of a cross allergy to other pyrazyl ketones and Pyrazolidinums is probable.

Agranulocytosis. At emergence of signs of an agranulocytosis, thrombocytopenia it is necessary to stop immediately administration of drug and to conduct a blood test research (including a leukocytic formula). Treatment has to be stopped before obtaining results of laboratory researches.

Pancytopenia. At development of a pancytopenia treatment has to be immediately stopped with the subsequent control of blood test before its normalization. The patient has to be informed on need of the address to the doctor if during treatment there are signs and symptoms testimonial of pathological change of blood (for example, an indisposition, an infection, constant fever, bruises, bleeding, pallor).

Anaphylactic / anaphylactoid reactions. At the choice of a way of introduction it is important to remember that parenteral administration of anesthetics is connected with higher risk of anaphylactic or anaphylactoid reactions.

The risk of potentially heavy anaphylactoid reactions to analginum considerably increases at patients with:

- asthma syndrome on analgetics or a Quincke's disease on non-narcotic analgesics,

- bronchial asthma, especially with accompanying rinosinusity and polyps in a nose,

- chronic small tortoiseshell,

- intolerance of dyes (for example, tartrazine) and preservatives (for example, benzoates)

- intolerance of alcohol. Such patients can react to alcoholic beverages even in small amounts with such symptoms as sneezing, the watering eyes and strong face reddening. Such intolerance of alcohol can be a symptom of earlier not diagnosed asthma on analgetics.

The acute anaphylaxis usually develops at predisposed patients. Therefore, special attention needs to be paid to patients with asthma or an atopy.

Heavy skin reactions. When using analginum life-threatening skin reactions, such as Stephens-Johnson's syndrome and a toxic epidermal necrolysis were registered. At emergence of symptoms or signs of a syndrome of Stephens-Johnson or a toxic epidermal necrolysis (for example, the progressing skin rash, it is frequent with bubbles or damages of a mucous membrane), treatment by analginum needs to be stopped immediately. Patients have to be informed on signs and symptoms and to monitor carefully changes from skin, especially in the first weeks of treatment.

The isolated hypotensive reactions. Analginum can lead to hypotensive reactions. These reactions can be dependent on a dose. Usually these reactions arise at parenteral administration, but not enteral. The risk of such reactions is also increased:

- at a bystry intravenous injection;

- at patients with the previous hypotension, dehydration or dehydration, unstable arterial pressure or with the beginning circulatory unefficiency (for example, at patients with multiple injuries or heart attack),

- at patients with high temperature.

Careful survey and careful control is required from similar patients. Preventive measures (such as blood circulation stabilization) can be necessary for decrease in risk of hypotensive reactions.

In exceptional cases analginum can be used at patients at whom a lowering of arterial pressure it is necessary to avoid at any cost, for example, at heavy coronary heart disease or the corresponding stenosis of brain arteries, only after careful control of indicators of a hemodynamics.

At patients with a renal or liver failure analginum use perhaps only after careful assessment of a ratio of advantage and risk and use of the appropriate measures of precaution (see the section "Route of Administration and Doses"). It is necessary to collect the anamnesis at the patient before administration of analginum. At patients with the increased risk of development of anaphylactic reactions analginum can be used only after careful assessment of potential advantage and risk. It is necessary to apply analginum in this situation under careful medical control and possibilities of rendering the emergency help.

Pregnancy. Adequate data on use of analgetik during pregnancy are absent. Metamizol gets through a placental barrier. In researches on animals analginum did not cause development of teratogenic effects. Due to the lack of the conducted adequate researches in public, analginum in the second and first trimester of pregnancy has to be applied only after strict assessment of advantage and risk.

In spite of the fact that analginum is weak inhibitor of synthesis of prostaglandins, there is a possibility of premature closing of an arterial channel and development of perinatal complications due to decrease in aggregation of thrombocytes at the child and mother. In this regard analginum is contraindicated during the last trimester of pregnancy.

Lactation period. Metabolites of analginum are allocated with breast milk therefore it is necessary to refuse breastfeeding within    48 hours after analginum reception.

Use in pediatrics. Use of analginum for children in the first 3 months of life in view of the increased risk of development of renal failures is not recommended.

Prolonged use of analginum (more than 7 days). In need of regular use of analginum over 5 days it is necessary to control a pattern of peripheral blood weekly.

Acute pain in a stomach. Use of analginum for stopping of an acute pain in a stomach before clarification of its reason is not recommended.

Use at persons with pathology of cardiovascular system. Careful control of a hemodynamics, especially at patients with the level of systolic pressure below 100 mm hg, diseases of kidneys in the anamnesis (pyelonephritis and a glomerulonephritis), and also at persons with alcohol addiction is necessary.

Influence on ability to driving of motor transport and control of mechanisms. The recommended range of doses does not influence concentration and speed of response. As precautionary measures it is necessary to avoid driving of cars, vehicles or other dangerous types of activity at reception of high doses. It belongs, in particular, and to a combination to alcohol.

Removal with urine of products of biotransformation of analginum can cause red coloring of urine which has no clinical value and disappears after medicine cancellation.

Side effects:

Frequency of the possible side effects which are listed below is defined as follows: very often (≥1/10), it is frequent (≥1/100 to <1/10), infrequently (≥1/1000 to <1/100), is rare (≥1/10 000do <1/1 000), is very rare (<1/10 000), it is unknown - it cannot be estimated on the basis of the available data.

Diseases of blood and lymphatic system: seldom: leukopenia; very seldom: an agranulocytosis, including cases from the death, thrombocytopenia, it is unknown: aplastic anemia, a pancytopenia, including cases from the death. These reactions can also arise at reception of analginum in the previous cases without complications.

There are several signs of the increased risk of development of an agranulocytosis at analginum reception more than a week.

This reaction of a dozozavisim can also develop in any period of treatment. It is shown by high temperature, a fever, a pharyngalgia, swallowing difficulty, an inflammation of area of a mouth, nose, throat, genital or proctal area. The patients receiving antibiotics, can have minimum expressed these symptoms. Lymph nodes and a spleen decreases or is absent. Considerably the blood sedimentation rate raises, the quantity considerably decreases or completely granulocytes disappear from peripheral blood. The amount of hemoglobin, erythrocytes and thrombocytes usually remains normal.

It is necessary to stop immediately administration of drug, without waiting for results of laboratory diagnostic tests at unexpected deterioration in the general state, existence of not stopped or recurrent fever, painful damages of a mucous membrane, especially oral cavities, a nose and a throat.

At development of a pancytopenia it is necessary to stop immediately treatment by analginum with the subsequent monitoring developed blood test before its normalization.

Diseases of immune system: seldom: anaphylactic or anaphylactoid reactions *; very seldom: "aspirinovy" asthma.

At patients about intolerance of analgetik development of attacks of asthma is possible. Frequency is not known: acute anaphylaxis *.

* These reactions arise at parenteral use more often, are serious and life-threatening and can lead to a lethal outcome in certain cases. Can develop also when the previous use of analginum took place without complications.

Such reactions can develop in time of an injection or right after administration of drug, and also in several hours. Preferential these reactions develop within the first hour after introduction. Easier reactions are shown by reactions from skin and mucous (for example, an itch, burning, reddening, urticaria, hypostasis), an asthma and, seldom, symptoms from digestive tract. Severe forms can be shown by a generalized small tortoiseshell, a Quincke's edema (including throats), a heavy bronchospasm, disturbance of a heart rhythm, arterial hypotension (increase in arterial pressure can sometimes precede), vascular shock. At emergence of skin reactions use of analginum has to be stopped.

From cardiovascular system. Sometimes: hypotensive reactions in time or after use, not connected with use of others pharmacological of means or development anaphylactic / anaphylactoid reactions. Bystry intravenous administration increases risk of development of hypotensive reaction.

At a hyperthermia administration of drug can lead to a critical dozozavisimy lowering of arterial pressure without any other symptoms of reactions of hypersensitivity.

Diseases of skin and hypodermic cellulose: infrequently: the fixed erythema; seldom: rash (for example, makulopapulezny rash); very seldom: Stephens-Johnson's syndrome or a toxic epidermal necrolysis (it is necessary to stop treatment, see the section "Precautionary measures").

Diseases of kidneys and urinary tract: very seldom: sharp deterioration in function of kidneys which can be followed by a proteinuria, oligo-or an anury, up to development of an acute renal failure, acute intersticial nephrite.

The general diseases and reactions in an injection site: coloring of urine in red color. Perhaps, it is connected with existence in urine in low concentration of a harmless metabolite of analginum.

Interaction with other medicines:

Analginum can cause decrease in concentration of cyclosporine in blood serum. It is necessary to monitorirovat concentration of cyclosporine at co-administration of analgetik.

At co-administration of analgetik and aminazine development of a heavy hypothermia is possible.

Purpose of metamizol against the background of reception of a methotrexate can lead to increase in hematologic toxicity of a methotrexate, especially at elderly patients. It is recommended to avoid purpose of this combination.

The possibility of interaction of derivatives of pyrazyl ketone with peroral anticoagulants, captopril, lithium and Triamterenum, and also influence on efficiency of anti-hypertensive drugs and diuretics is established. Extent of the described interactions for analginum is not known.

Because of potential incompatibility it is not recommended to mix injection solution of analginum with other medicines for injections or infusions (see also section "Route of Administration and Doses").

Contraindications:

- hypersensitivity to active agent or other derivatives of pyrazyl ketone or Pyrazolidinum (including patients at whom the agranulocytosis after use of these drugs developed) or any other component of drug;

- at patients with aspirinovy asthma in the anamnesis or a syndrome of intolerance of analgetics (a small tortoiseshell, a Quincke's disease), that is at patients with a bronchospasm or with other forms of anaphylactoid reactions to salicylates, paracetamol or other non-narcotic analgesics, such as diclofenac, an ibuprofen, indometacin or Naproxenum;

- oppression of function of marrow (for example, after treatment by cytostatics) or diseases of the hemopoietic system;

- genetic deficit glyukozo-6-fosfatdegidrogenazy (hemolysis);

- the acute alternating hepatic porphyria (risk of development of an attack of a porphyria);

- last trimester of pregnancy;

- breastfeeding period;

- newborns and children aged up to 3 months or with body weight less than 5 kg (there is no information on use);

- children aged from 3 months up to 11 months for an intravenous way of introduction;

- arterial hypotension and/or unstable hemodynamics.

With care. Long alcohol abuse. Intravenous administration by the patient with systolic arterial pressure below 100 mm hg or at instability of blood circulation (for example, against the background of a myocardial infarction, a multiple injury, the beginning shock).

Overdose:

Symptoms: a hypothermia, the expressed lowering of arterial pressure, heartbeat, an asthma, a sonitus, nausea, vomiting, a gastralgia, weakness, an oliguria, an anury, drowsiness, nonsense, consciousness disturbance, tachycardia, a convulsive syndrome, development of an acute agranulocytosis, hemorrhagic syndrome, an acute renal and liver failure, paralysis of respiratory muscles is possible.

Treatment: induction of vomiting, probe gastric lavage, purpose of salt laxatives, absorbent carbon. Carrying out an artificial diuresis, hemodialysis, blood alkalization, the symptomatic therapy directed to maintenance of the vital functions. At development of a convulsive syndrome carry out intravenous administration of a diazelam and high-speed barbiturates.

Storage conditions:

In the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 3 years. Not to use medicine after the termination of a period of validity.

Issue conditions:

According to the recipe

Packaging:

In ampoules of 1 or 2 ml in packaging No. 10, No. 10 x 1.